Epidermal Growth Factor-Induced Nuclear Factor κ B Activation: A Major Pathway of Cell-Cycle Progression in Estrogen-Receptor Negative Breast Cancer Cells

• Published in: Proceedings of the National Academy of Sciences - PNAS 2000-07, Vol.97 (15), p.8542-8547
• Main Authors: Biswas, Debajit K., Cruz, Antonio P., Gansberger, Eva, Pardee, Arthur B.
• Format: Article
• Language: English
• Subjects: 3T3 cells; Antibodies; Biological Sciences; Breast cancer; Breast Neoplasms - metabolism; Carbazoles - pharmacology; Cell Cycle; Cell growth; Cell lines; Cell nucleus; Cells; Cyclin D1 - metabolism; Cyclin D1 - physiology; Epidermal cells; Epidermal Growth Factor - metabolism; Epidermal Growth Factor - pharmacology; Epithelial cells; ErbB Receptors - metabolism; Female; Humans; Indoles - pharmacology; Kinetics; NF-kappa B - antagonists & inhibitors; NF-kappa B - metabolism; Receptors; Receptors, Estrogen - metabolism; Signal Transduction; Tumor Cells, Cultured
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.97.15.8542

The epidermal growth factor (EGF) family of receptors (EGFR) is overproduced in estrogen receptor (ER) negative (-) breast cancer cells. An inverse correlation of the level of EGFR and ER is observed between ER- and ER positive (+) breast cancer cells. A comparative study with EGFR-overproducing ER- and low-level producing ER+ breast cancer cells suggests that EGF is a major growth-stimulating factor for ER- cells. An outline of the pathway for the EGF-induced enhanced proliferation of ER- human breast cancer cells is proposed. The transmission of mitogenic signal induced by EGF-EGFR interaction is mediated via activation of nuclear factor κ B (NF-κ B). The basal level of active NF-κ B in ER- cells is elevated by EGF and inhibited by anti-EGFR antibody (EGFR-Ab), thus qualifying EGF as a NF-κ B activation factor. NF-κ B transactivates the cell-cycle regulatory protein, cyclin D1, which causes increased phosphorylation of retinoblastoma protein, more strongly in ER- cells. An inhibitor of phosphatidylinositol 3 kinase, Ly294-002, blocked this event, suggesting a role of the former in the activation of NF-κ B by EGF. Go6976, a well-characterized NF-κ B inhibitor, blocked EGF-induced NF-κ B activation and up-regulation of cell-cycle regulatory proteins. This low molecular weight compound also caused apoptotic death, predominantly more in ER- cells. Thus Go6976 and similar NF-κ B inhibitors are potentially novel low molecular weight therapeutic agents for treatment of ER- breast cancer patients.